ORPHA: 3303;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 5q35.3 | Congenital heart defects, multiple types, 7 | 618780 | Autosomal dominant | 3 | FLT4 | 136352 |
A number sign (#) is used with this entry because of evidence that multiple types of congenital heart defects (CHTD7) are caused by heterozygous mutation in the FLT4 gene (136352) on chromosome 5q35.
For a discussion of genetic heterogeneity of multiple types of congenital heart defects, see 306955.
Multiple types of congenital heart defects-7 (CHTD7) is an autosomal dominant disorder with incomplete penetrance characterized mainly by tetralogy of Fallot but also including right-sided aortic arch, absent pulmonary valve, and other cardiac abnormalities (Jin et al., 2017, Reuter et al., 2019).
Jin et al. (2017) reported 10 families with nonsense or frameshift mutations in FLT4 and congenital heart defects. The phenotype in 9 of 10 probands and 3 of 4 affected relatives was tetralogy of Fallot. Other heart defects included pulmonary stenosis or atresia, absent pulmonary valve, right aortic arch, double aortic arch, and major aortopulmonary collateral arteries. Other features included unspecified extracardiac manifestations in 1 patient; the presence of neurodevelopmental disorders was reported as negative in 2 patients and 'unknown' in 7 in a supplementary table.
Reuter et al. (2019) reported 9 families with tetralogy of Fallot who had novel mutations in the FLT4 gene. In addition to cardiac defects, several patients had anxiety and depression.
The transmission pattern of CHTD7 in 2 families reported by Jin et al. (2017) was consistent with autosomal dominant inheritance. The heterozygous mutations in the FLT4 gene that were identified in 2 patients with CHTD7 by Jin et al. (2017) occurred de novo. In 6 probands, the mutation was inherited from an unaffected parent, indicating incomplete penetrance.
In a cohort of 2,871 probands with congenital heart disease, comprising 2,645 parent-offspring trios and 226 singletons, Jin et al. (2017) performed whole-exome sequencing and identified 10 probands who were heterozygous for frameshift or nonsense mutations in the FLT4 gene (e.g., 136352.0013, 136352.0014). In 2 probands the mutations arose de novo, and in 2 probands the mutations were inherited from an affected parent; however, in 6 probands, the mutation was inherited from an unaffected parent.
Reuter et al. (2019) sequenced 175 adult patients with tetralogy of Fallot and 56 with other congenital cardiac anomalies for loss-of-function and deleterious mutations in FLT4 and other VEGF pathway genes. They identified 9 (5.1%) probands with novel FLT4 variants (e.g., 136352.0014-136352.0017), all of whom came from the group of individuals with tetralogy of Fallot. Seven of the variants were predicted to have a loss-of-function effect, implicating haploinsufficiency, and comprised 2 stopgain, 3 frameshift, 1 splice site, and 1 multiexon deletion mutation; the other 2 mutations, a missense and an in-frame deletion, were predicted to be deleterious.
Jin, S. C., Homsy, J., Zaidi, S., Lu, Q., Morton S., DePalma, S. R., Zeng, X., Qi, H., Chang, W., Sierant, M. C., Hung, W.-C., Haider, S., and 33 others. Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands. Nature Genet. 49: 1593-1601, 2017. [PubMed: 28991257] [Full Text: https://doi.org/10.1038/ng.3970]
Reuter, M. S., Jobling, R., Chaturvedi, R. R., Manshaei, R., Costain, G., Heung, T., Curtis, M., Hosseini, S. M., Liston, E., Lowther, C., Oechslin, E., Sticht, H., and 9 others. Haploinsufficiency of vascular endothelial growth factor related signaling genes is associated with tetralogy of Fallot. Genet. Med. 21: 1001-1007, 2019. [PubMed: 30232381] [Full Text: https://doi.org/10.1038/s41436-018-0260-9]